There are more than 300,000 patients receiving chronic hemodialysis (CHD) therapy in the United States, which is estimated to rise to over 400,000 patients by 2010. Of those current patients, an estimated 11,612 veterans receive hemodialysis through Veterans Administration. Unfortunately, patients receiving chronic hemodialysis therapy, suffer from unacceptably high death rates. Epidemiological studies indicate that protein energy wasting (PEW), a unique and highly prevalent nutritional abnormality primarily characterized by increased protein breakdown in the skeletal muscle compartment in CHD patients, is one most important determinants of this poor outcome. Although the etiology and mechanisms leading to PEW in CHD patients are complex and mostly ill-defined, two well-recognized and presumably interrelated nutritional abnormalities, insulin resistance and chronic inflammation, are likely to play critical roles in the pathogenesis of this condition. Insulin resistance in CHD patients has been characterized using euglycemic insulin clamp techniques. Multiple in vitro and in vivo studies demonstrate the anabolic effects of insulin that extend beyond simple carbohydrate metabolism. In this context, data from our laboratory indicate the critical importance of insulin resistance as a major mediator of accelerated protein breakdown in CHD patients. Consistent with this hypothesis, recent in vitro data indicate that treatment with an insulin sensitizer (PPARg agonist rosiglitazone) suppressed muscle proteolysis. These in vitro and in vivo experimental data are further supported by recent epidemiological data showing significantly lower rate of all-cause mortality at one year of follow up among incident CHD patients with non-insulin requiring diabetes on thiazolidinediones (TZD). Chronic inflammation, a condition known to cause muscle catabolism in animal models, has a strong association with advanced kidney disease in epidemiological studies. Chronic inflammation is also known to induce insulin resistance, primarily by the induction of pro-inflammatory cytokines. Further, inflammation and insulin resistance share common signaling pathways when mediating muscle catabolism. Thus, it is reasonable to speculate that chronic inflammation of advanced kidney disease mediates its protein catabolic effects by inducing insulin resistance of protein metabolism at both the physiological and cellular levels. In this application, we hypothesize that the chronic inflammatory component of protein energy wasting in CHD patients is mediated by insulin resistance. The overarching goal of this grant application is to elucidate the mechanisms by which chronic inflammation and insulin resistance influence the development of protein energy wasting in CHD patients. We will test our hypotheses by the following specific aims: Specific Aim 1: To characterize the physiological mechanisms by which chronic inflammation and insulin resistance mediate muscle protein breakdown in CHD patients; Specific Aim 2: To test the hypothesis that inhibiting inflammatory response by administration of an Interleukin-1 receptor antagonist or increasing insulin sensitivity by administration of a PPARg agonist will improve net protein metabolism. If successful, our proposed studies will have great potential to influence clinical practices in CHD patients because the proposed intervention protocol would be easily accessible and could ultimately lead to improvements in the hospitalization and death rates. Hence, it is expected that the results of this proposal will have a great impact on Veterans' Health Care and make important contributions to the research mission of the Department of Veterans Administration, providing new knowledge in metabolic and nutritional aspects of end-stage renal disease patients.